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Effects of Methylphenidate and MDMA on Appraisal of Erotic Stimuli and Intimate Relationships

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Effects of Methylphenidate and MDMA on Appraisal of Erotic Stimuli and Intimate Relationships Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2015 Effects of methylphenidate and MDMA on appraisal of pictures oferotic stimuli and intimate relationships Schmid, Y ; Hysek, Cédric M ; Preller, Katrin H ; Bosch, Oliver G ; Bilderbeck, A C ; Rogers, R D ; Quednow, Boris B ; Liechti, Matthias E DOI: https://doi.org/10.1016/j.euroneuro.2014.11.020 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-106578 Journal Article Accepted Version Originally published at: Schmid, Y; Hysek, Cédric M; Preller, Katrin H; Bosch, Oliver G; Bilderbeck, A C; Rogers, R D; Quednow, Boris B; Liechti, Matthias E (2015). Effects of methylphenidate and MDMA on appraisal of pictures of erotic stimuli and intimate relationships. European Neuropsychopharmacology, 25:17-25. DOI: https://doi.org/10.1016/j.euroneuro.2014.11.020 *Revised Manuscript Schmid et al. Effects of methylphenidate and MDMA on appraisal of erotic stimuli and intimate relationships Short title: methylphenidate, MDMA and sexual arousal 1 1 2 2 3 Yasmin Schmid , Cédric M. Hysek , Katrin H. Preller , Oliver G. Bosch , Amy C. Bilderbeck , Robert D. Rogers4, Boris B. Quednow2, Matthias E. Liechti*,1 1Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel and University of Basel, Switzerland; 2Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland 3Department of Psychiatry, Oxford University, UK 4School of Psychology, Bangor University, UK *Correspondence: Matthias E. Liechti, Division of Clinical Pharmacology, University Hospital Basel, Hebelstrasse 2, CH-4031 Basel, Switzerland; E-mail: [email protected] Word count: Abstract: 216; Introduction: 698, Discussion: 1644, Manuscript: 4364 words References: 51 Tables and Figures: Tables: 2; Figures: 2 Trial registration: Clinical trials.gov: http://www.clinicaltrials.gov/ct2/show/NCT01616407 1 Schmid et al. Abstract Methylphenidate mainly enhances dopamine neurotransmission whereas 3,4- methylenedioxymethamphetamine (MDMA, “ecstasy”) mainly enhances serotonin neurotransmission. However, both drugs also induce a weaker increase of cerebral noradrenaline exerting sympathomimetic properties. Dopaminergic psychostimulants are reported to increase sexual drive, while serotonergic drugs typically impair sexual arousal and functions. Additionally, serotonin has also been shown to modulate cognitive perception of romantic relationships. Whether methylphenidate or MDMA alter sexual arousal or cognitive appraisal of intimate relationships is not known. Thus, we evaluated effects of methylphenidate (40mg) and MDMA (75mg) on subjective sexual arousal by viewing erotic pictures and on perception of romantic relationships of unknown couples in a double-blind, randomized, placebo-controlled, crossover study in 30 healthy adults. Methylphenidate, but not MDMA, increased ratings of sexual arousal for explicit sexual stimuli. The participants also sought to increase the presentation time of implicit sexual stimuli by button press after methylphenidate treatment compared with placebo. Plasma levels of testosterone, estrogen, and progesterone were not associated with sexual arousal ratings. Neither MDMA nor methylphenidate altered appraisal of romantic relationships of others. The findings indicate that pharmacological stimulation of dopaminergic but not of serotonergic neurotransmission enhances sexual drive. Whether sexual perception is altered in subjects misusing methylphenidate e.g., for cognitive enhancement or as treatment for attention deficit hyperactivity disorder is of high interest and warrants further investigation. Keywords: MDMA, methylphenidate, sexual arousal, couples appraisal 2 Schmid et al. Introduction Methylphenidate is a stimulant drug used for the treatment of attention deficit hyperactivity disorder, but it is also misused as a club drug and a cognitive enhancer (Maier et al., 2013). 3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”) is a popular recreational drug used primarily because of its empathogenic properties, i.e. the drug increases feelings of sociability and closeness to others (Hysek et al., 2013; Morgan et al., 2013). Additionally, both drugs also have psychostimulant properties (Hysek et al., 2014). It is well recognized that psychoactive substances affect sexual behavior. Users of psychostimulants including cocaine and methamphetamine report increased sexual desire and arousal and enhanced sexual pleasure (Frohmader et al., 2010; Rawson et al., 2002; Semple et al., 2002). In contrast, ecstasy users described inconsistent effects of MDMA on sexual desire (McElrath, 2005; Passie et al., 2005; Theall et al., 2006). Specifically, most users report no desire for penetrative sex but only increased feelings of sensuality, whereas some (in particular gay and bisexual females) use MDMA in particular for sexual enhancement (McElrath, 2005). In another survey, similar proportions of users reported increased or decreased interest in initiating sexual activity while on MDMA (Buffum and Moser, 1986). Additionally, sexual performance seems to be consistently impaired by the drug (Buffum and Moser, 1986; Passie et al., 2005; Zemishlany et al., 2001). Thus, MDMA induces well-being and feelings of closeness to others (Hysek et al., 2013) accompanied by a sensual rather than a sexual enhancement (Passie et al., 2005). However, research on psychoactive drug use and sexual behavior is typically based on interviews of drug users and has mainly focused on sexual risk taking (McElrath, 2005; Rawson et al., 2002; Semple et al., 2002; Theall et al., 2006). Few studies have objectively evaluated sexual arousal in stimulant drug users (Aguilar de Arcos et al., 2008) or investigated the effects of acute administration of a psychostimulant on sexual perception (Volkow et al., 2007). In particular, intravenous administration of methylphenidate at a high dose of 0.5 mg/kg body weight has been shown to enhance self-reported sexual desire 3 Schmid et al. (Volkow et al., 2007) while administration of a moderate oral dose of methylphenidate (20 mg) had no effects (Volkow et al., 2007). Finally, to our knowledge there are no experimental data on the effects of MDMA on sexual perception and arousal. Methylphenidate increases dopamine (DA) and norepinephrine (NE) neurotransmission by DA and NA reuptake inhibition (Schmeichel and Berridge, 2013), while MDMA mainly releases serotonin (5-hydroxytryptamine, 5-HT) but also NE (Hysek et al., 2012b). While DA is thought to facilitate sexual drive, 5-HT is stated to inhibit sexual arousal and function (Fabre-Nys, 1998; Frohmader et al., 2010; Melis and Argiolas, 1995; Passie et al., 2005; Pfaus, 2009; Zemishlany et al., 2001). For example, dopaminergic antiparkinson therapy is associated with hypersexuality (Kelley et al., 2012; Uitti et al., 1989; Weintraub et al., 2010) whereas decreased libido and sexual dysfunction are common adverse effects of serotonergic antidepressants (Serretti and Chiesa, 2009). Accordingly, we hypothesized that methylphenidate (40 mg), predominantly enhancing DA, would increase sexual arousal in a Sexual Arousal Task (SAT), while MDMA (75 mg), mainly increasing 5-HT, would not. Because sex hormones may alter sexual arousal (Meston and Frohlich, 2000), we measured testosterone, estrogen, and progesterone plasma levels and explored possible associations with sexual arousal ratings. Besides from having effects on sexual desire and emotion, psychoactive drugs may also influence aspects of the cognitive appraisal of romantic partnerships. For example, MDMA has been shown to acutely alter related components of social cognition including recognition of facial emotions (Bedi et al., 2010; Hysek et al., 2012a; Hysek et al., 2013; Hysek et al., 2014; Kirkpatrick et al., 2014) and emotional empathy (Hysek et al., 2013; Kuypers et al., 2014; Schmid et al., 2014). Additionally, changes in 5-HT levels may influence cognitions sustaining intimate relationships. Specifically, healthy volunteers perceived photographed couples as being less intimate and romantic after lowering cerebral 5-HT levels by tryptophan depletion (Bilderbeck et al., 2011). In contrast, sub-chronic administration of the selective 5-HT reuptake inhibitor (SSRI) citalopram increased perceived 4 Schmid et al. worth of mutual trust in relationships and reduced importance attributed to physical and intimate aspects of the participants’ own relationship (Bilderbeck et al., 2014). We therefore evaluated the effect of a 5-HT releaser (MDMA) and a DA and NA reuptake inhibitor (methylphenidate) on cognitive appraisal of intimate relationships. We hypothesized that MDMA, but not methylphenidate, would increase ratings of intimacy and romance in the Couples Appraisal Task (CAT) (Bilderbeck et al., 2011; Bilderbeck et al., 2014) parallel to its 5-HT enhancing, empathogenic and prosocial effects (Hysek et al., 2013; Kirkpatrick et al., 2014). Experimental Procedures Experimental protocol We used a double-blind, placebo-controlled, cross-over design in 30 subjects each treated with methylphenidate (40mg), MDMA (75 mg), and placebo, resulting in 90 assessments. The order of the three experimental sessions was balanced (Latin Square design), and the washout periods between sessions were
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